Project Abstract Age-related macular degeneration (AMD) remains a leading cause of loss-of-vision that necessitates mechanistic studies of disease and the development of new therapeutics. Early AMD progresses to later, blinding forms following one of two divergent pathways: i) Atrophic AMD is associated with degeneration and death of retinal pigment epithelium (RPE); and ii) choroidal neovascularization (CNV) is associated with growth of new vessels under the retina. While there are treatments for CNV using anti-angiogenic drugs, there are no effective treatments for subretinal fibrosis (SRF). SRF is a complication of both end-stage and treated CNV that results in severe to profound visual impairment. To address this complication, our team invented a novel ?B-crystallin peptide nanoparticle (?BC-ELP) that markedly inhibits the progression of SRF. Elastin-like polypeptides (ELPs) are high molecular weight biocompatible biopolymers derived from human tropoelastin that retain a biologically-active fragment of the ?B-crystallin protein near the retina for extended periods, thus enabling their therapeutic efficacy. As supported by our preliminary data, we hypothesize that ?BC-ELP will prevent the progression of SRF compared to controls. We further hypothesize that the inhibitory effect of (?BC-ELP) on SRF decreases the generation of fibrosis-promoting, senescent cells and improves the regulation of mitochondrial metabolism by promoting oxidative phosphorylation. These hypotheses will be tested using the following Specific Aims: Aim #1. Characterize ocular pharmacokinetics of intravitreal ?BC- ELP in mouse and rabbit eyes. Aim #2. Characterize SRF and determine effect and time course of ?BC-ELP in laser model of CNV. Aim #3. Establish the mechanistic role of senescence cells in progression of SRF and the mechanism of its inhibition by ?BC-ELP. Aim #4. Establish the mechanistic role of mitochondrial bioenergetics and mitochondrial SMAD4 in SRF and the mechanism of its inhibition by ?BC-ELP.